Biologically active peptides function as hormones, paracrine regulators, or chemical neurotransmitters. These peptides are usually released by proteolysis of a larger, often inactive, precursor molecule. Neuropeptides perform many functions in the central nervous system (CNS) as neurotransmitters, neuromodulators, and neurotrophic factors (Stewart, J. M. and Hall, M. E. (1993) Agents Actions Suppl. 42:211-226). Neuropeptides are also important regulators of amine neurotransmitter release and can be identified as playing important roles in several pathological states (Stewart and Hall (1993) supra).
The tachykinins comprise a family of closely related peptides that participate in the regulation of diverse biological processes. They are characterized by the amino acid residue sequence-Phe-X-Gly-Leu-Met-NH.sub.2 at the C-terminus in which X represents an aromatic (Phe, Tyr) or branched aliphatic (Val, Ile) amino acid. The tachykinin peptides substance P (SP), neurokinin A (NKA), NKA(3-10), neuropeptide K, and neuropeptide .gamma. are produced from a single preprotachykinin gene, preprotachykinin A (PPT-A). Differential splicing of PPT-A mRNA yields .alpha.PPT-A, .beta.PPT-A, .gamma.PPT-A, and .delta.PPT-A mRNA species. Postranslational processing of the preproprotein gives rise to multiple active products both within a single cell and in different cells expressing the gene (c.f. Helke, C. J. (1990) FASEB J. 4:1606-1615; Nakanishi, S. (1987) Physiol. Rev. 67:1117-1142). N-terminally extended forms of SP and NKA, but not the mature peptides, are detected in measurable amounts in human cerebrospinal fluid (CSF) using high performance liquid chromatography (HPLC). It has been suggested that their levels in CSF can be used as markers of the activity in central SP and NKA neurons (Toresson, G. et al. (1993) Regul. Pept. 46:357-359). In mammals, SP and NKA cause vasodilation in the circulatory system, are involved in inflammation and immune processes, and play a role in the pathogenesis of allergic diseases (Otsuka, M. and Yoshioka, K. (1993) Physiol. Rev. 73:229-308).
A second preprotachykinin gene, PPT-B, encodes proneurokinin B (Kotani. H. et al. (1986) Proc. Natl. Acad. Sci. USA 83:7074-7078). Proteolytic cleavage of rat proneurokinin B yields neurokinin B (NKB) and a 30-residue peptide (Lang, S. and Sperk, G. (1995) Regul. Pept. 57:183-192). PPT-B mRNA and peptide products are differentially distributed throughout the CNS (particularly in the hypothalamus) and peripheral tissue (Helke, C. J. (1990) supra). PPT-B mRNAs have been isolated from bovine and rat brain, and the proteins share 75% amino acid residue identity (Kotani, H. et al. (1986) supra; Bonner, T. I. et al. (1987) Brain Res. 388:243-249).
NKB has been shown to be involved in a broad range of biological functions. Foe example, acute treatment of rats with synthetic rat NKB prevented a decline in cortical choline acetyltransferase activity associated with injection of N-methyl-D-aspartate into the nucleus basalis magnocellularis. NKB also attenuated impaired behavioral performance produced by entorhinalcortex lesions (Wenk, G. L. et al. (1997) Behav. Brain Res. 83:129-133). Levels of rat NKB mRNA and NKB-immunoreactivity in the granule cells of the rat hippocampus were enhanced following limbic epileptogenesis. It has been suggested that these changes may have profound effects on synaptic transmission and contribute to modulate hippocampal excitability (Schwarzer, C. et al. (1996) Brain Res. Brain Res. Rev. 22:27-50). Large amounts of NKB, but not of SP, or NKA, were found in tumors of the peripheral nervous system and it has been suggested that PPT-B gene expression predominates over that of PPT-A and may be used as a tumor marker of nervous tissue (McGregor, G. P. et al. (1990) FEBS Lett. 277:83-87). NKB induced airway mucus secretion in the rat, and an NKB agonist, [MePhe7]-NKB, caused contraction of guinea pig lung parenchymal strips in vitro (Wagner, U. et al. (1995) Life Sci. 57:283-289; Killingsworth, C. R. and Shore, S. A. (1995) Regul. Pept. 57:149-161). NKB modulates cellular biochemistry by interacting with NK-3, a G-protein coupled receptor, inducing second messenger pathways activated by Ca.sup.2+, inositoltrisphosphate, and diacylglycerol (Helke, C. J. et al. (1995) supra). The properties of the 30 residue peptide (preprotachykinin B(50-79)) are unknown.
The discovery of a new human preprotachykinin B and the polynucleotides encoding it satisfies a need in the art by providing new compositions which are useful in the diagnosis, prevention and treatment of neurological and neoplastic disorders.